Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents

Keith A. Monk, Rogelio Siles, Mallinath B. Hadimani, Benon E. Mugabe, J. Freeland Ackley, Scott W. Studerus, Klaus Edvardsen, Mary Lynn Trawick, Charles M. Garner, Monte R. Rhodes, George Pettit, Kevin G. Pinney

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

A series of analogs with nitro or serinamide substituents at the C-2′-, C-5′-, or C-6′-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization. The synthesis of these analogs typically featured a Wittig reaction between a suitably functionalized arylaldehyde and an arylphosphonium salt followed by separation of the resultant E- and Z-isomers. Several of these nitrogen-modified CA4 derivatives (both amino and nitro) demonstrate significant inhibition of tubulin assembly as well as cytotoxicity and in vivo blood flow reduction. 2′-Aminostilbenoid 7 and 2′-amino-3′-hydroxystilbenoid 29 proved to be the most active in this series. Both compounds, 7 and 29, have the potential for further pro-drug modification and development as vascular disrupting agents for treatment of solid tumor cancers and certain ophthalmological diseases.

Original languageEnglish (US)
Pages (from-to)3231-3244
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number9
DOIs
StatePublished - May 1 2006

    Fingerprint

Keywords

  • Anti-cancer
  • Combretastatin
  • Inhibitors of tubulin assembly
  • Pro-drug constructs
  • Tubulin
  • Vascular disrupting agents

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Monk, K. A., Siles, R., Hadimani, M. B., Mugabe, B. E., Ackley, J. F., Studerus, S. W., Edvardsen, K., Trawick, M. L., Garner, C. M., Rhodes, M. R., Pettit, G., & Pinney, K. G. (2006). Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents. Bioorganic and Medicinal Chemistry, 14(9), 3231-3244. https://doi.org/10.1016/j.bmc.2005.12.033